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With the constant development of new antibiotics, selective pressure is a force to reckon
when investigating antibiotic resistance. Although advantageous for medical treatments,
it leads to increasing resistance. It is essential to use more potent and toxic antibiotics.
Enzymes capable of hydrolyzing antibiotics are among the most common ways of
resistance and TEM variants have been detected in several resistant isolates. Due to the
rapid evolution of these variants, complex phenotypes have emerged and the need to
understand their biological activity becomes crucial.
To investigate the biochemical properties of TEM-180 and TEM-201 several
computational methodologies have been used, allowing the comprehension of their
structure and catalytic activity, which translates into their biological phenotype.
In this work we intent to characterize the interface between these proteins and the
several antibiotics used as ligands. We performed explicit solvent molecular dynamics
(MD) simulations of these complexes and studied a variety of structural and energetic
features.
The interfacial residues show a distinct behavior when in complex with different
antibiotics. Nevertheless, it was possible to identify some common Hot Spots among
several complexes – Lys73, Tyr105 and Glu166. The structural changes that occur during
the Molecular Dynamic (MD) simulation lead to the conclusion that these variants have
an inherent capacity of adapting to the various antibiotics. This capability might be the
reason why they can hydrolyze antibiotics that have not been described until now to be
degraded by TEM variants. The results obtained with computational and experimental
methodologies for the complex with Imipenem have shown that in order to this type of
enzymes be able to acylate the antibiotics, they need to be capable to protect the ligand
from water molecules.
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Instituto Politécnico do Porto. Escola Superior de Tecnologia da Saúde do Porto